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in their recent study Arends and colleagues demonstrate a significant 2.8-fold increased risk for the formation of neutralizing anti-drug antibodies (ADA) in male patients with Fabry disease (FD) when treated with agalsidase-beta (1.0 mg/kg every other week) compared to agalsidase-alfa (0.2 mg/kg every other week).[1] Interestingly, Rombach and colleagues and later Smid and colleagues reported no significant differences in a humoral response, when using an identical dosage of 0.2 mg/kg for both drugs. [2,3] Hence, the 5-fold higher dosage of agalsidase-beta and not the compound itself seems to be an important trigger for antibody formation. However, none of the studies determined the cross reactive immunological status, which is crucial for the risk of a humoral response. The subgroup analysis of patients with ADAs by Arends and colleagues also revealed a better biochemical response to agalsidase-beta at 1.0 mg/kg in terms of decreasing lyso-Gb3 levels.[1] The authors propose that a saturation of antibody titers due to the 5-fold higher dosage might lead to the observed effect. In this respect, we recently demonstrated that antibodies can be supersaturated and that appropriate (i.e. individually optimized) enzyme dosages can overcome ADA titers already during infusions, which may result in improved patients’ outcome.[4] However, in the same study, we also demonstrated that even in patients treated with low-dose enzyme replacement therapy ADA titers can...

in their recent study Arends and colleagues demonstrate a significant 2.8-fold increased risk for the formation of neutralizing anti-drug antibodies (ADA) in male patients with Fabry disease (FD) when treated with agalsidase-beta (1.0 mg/kg every other week) compared to agalsidase-alfa (0.2 mg/kg every other week).[1] Interestingly, Rombach and colleagues and later Smid and colleagues reported no significant differences in a humoral response, when using an identical dosage of 0.2 mg/kg for both drugs. [2,3] Hence, the 5-fold higher dosage of agalsidase-beta and not the compound itself seems to be an important trigger for antibody formation. However, none of the studies determined the cross reactive immunological status, which is crucial for the risk of a humoral response. The subgroup analysis of patients with ADAs by Arends and colleagues also revealed a better biochemical response to agalsidase-beta at 1.0 mg/kg in terms of decreasing lyso-Gb3 levels.[1] The authors propose that a saturation of antibody titers due to the 5-fold higher dosage might lead to the observed effect. In this respect, we recently demonstrated that antibodies can be supersaturated and that appropriate (i.e. individually optimized) enzyme dosages can overcome ADA titers already during infusions, which may result in improved patients’ outcome.[4] However, in the same study, we also demonstrated that even in patients treated with low-dose enzyme replacement therapy ADA titers can be supersaturated.[4] Therefore, we conclude that assessments of individual antibody titers should be performed to determine optimal enzyme dosages for supersaturation of present antibodies and thus probably resulting in higher therapy efficiency and improved disease progression.